Cell Host & Microbe

Review

The Impact of Dietary Fiber on Gut

Microbiota in Host Health and Disease
€ckhed1,4,*
Kassem Makki,1 Edward C. Deehan,2 Jens Walter,2,3 and Fredrik Ba
1Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska

University Hospital, Gothenburg, Sweden

2Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada
3Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
4Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of

Health Sciences, University of Copenhagen, Copenhagen, Denmark

*Correspondence: fredrik@wlab.gu.se
https://doi.org/10.1016/j.chom.2018.05.012

Food is a primordial need for our survival and well-being. However, diet is not only essential to maintain
human growth, reproduction, and health, but it also modulates and supports the symbiotic microbial com-
munities that colonize the digestive tract—the gut microbiota. Type, quality, and origin of our food shape
our gut microbes and affect their composition and function, impacting host-microbe interactions. In this
review, we will focus on dietary fibers, which interact directly with gut microbes and lead to the production
of key metabolites such as short-chain fatty acids, and discuss how dietary fiber impacts gut microbial ecol-
ogy, host physiology, and health. Hippocrates’ notion ‘‘Let food be thy medicine and medicine be thy food’’
remains highly relevant millennia later, but requires consideration of how diet can be used for modulation of
gut microbial ecology to promote health.

Introduction colorectal cancer (CRC), allergies, autoimmune diseases, and

Our gut harbors trillions of microbes representing all kingdoms of
life that are essential for host development and physiology. This
‘‘gut microbiota’’ constitutes a complex community that inter-
acts with each other and with the host to modulate biological
processes essential for health. Our understanding of the biolog-
ical roles of the gut microbiome, which include modulating juve-
nile growth (Schwarzer et al., 2016), maturation of the immune
system (Rescigno, 2014), and modulation of glucose and lipid
metabolism (Ba €ckhed et al., 2004), has increased dramatically
in the past decade.
The microbiome contributes to homeostatic regulation in
different tissues in our body (Schroeder and Ba €ckhed, 2016).
However, although the overall interrelationship of humans with
their microbiota can be considered a mutualistic symbiosis (Wal-
ter et al., 2011), eubiosis, which refers to a healthy balance of the
microbes in the gut, can be disrupted, leading to the develop-
ment of various chronic diseases with an underlying inflamma-
tory condition (Hand et al., 2016). Most microbiome-linked
pathologies have dramatically increased over the past century,
suggesting that a change in lifestyle might disrupt gut microbiota
symbiosis due to the loss of beneficial, protective microbes
(Logan et al., 2016). In fact, Western-style diet, low in micro-
biota-accessible carbohydrates (MACs), may irreversibly reduce
microbial diversity and lead to the disappearance of specific
bacterial species in the digestive system (Sonnenburg et al.,
2016). Accordingly, the low intake of dietary fibers and the
increased amounts of fat and sugar in our food, typical for a
Westernized lifestyle and nutrition, may at least in part contribute
to depletion of specific bacterial taxa (Sonnenburg and Sonnen-
burg, 2014). These alterations may result in dysfunctions,
contributing to the increase in the development of chronic
inflammatory diseases such as intestinal bowel disease (IBD),
obesity and its associated pathologies. These diseases can, at
least in part, be prevented by dietary fiber, arguing for attempts
to close the ‘‘fiber gap’’ through adjustment of human diet (Dee-
han and Walter, 2016). Here we will discuss how dietary fiber
impacts gut microbial ecology, host physiology, and health by
specifically focusing on mechanisms by which a low-fiber diet
disrupts the microbial ecosystem and leads to a predisposition
to chronic inflammatory diseases.
Dietary Fibers: Definitions, Characteristics, and Origin
The definition of dietary fiber has been a matter of debate and
has evolved over the last decade (Jones, 2014). Most countries
adopted the definition of the Codex Alimentarius commission
from 2009, which defines dietary fiber as edible carbohydrate
polymers with three or more monomeric units that are resistant
to the endogenous digestive enzymes and thus neither hydro-
lyzed nor absorbed in the small intestine, and that belong to
the following categories: (1) edible carbohydrate polymers natu-
rally occurring in foods such as fruits, vegetables, legumes, and
cereals; (2) edible carbohydrate polymers obtained from food
raw materials by physical, enzymatic, and chemical means that
have a proven physiological benefit; and (3) synthetic carbohy-
drate polymers with a proven physiological benefit. Although
most national authorities adhere to this definition, some differ-
ences are found between dietary fiber definitions, and they
mainly concern (1) considering some non-carbohydrates such
as lignin and other substances present in cell walls linked to
polysaccharides as dietary fibers (Stephen et al., 2017) and (2)
the minimum number of carbohydrate monomers to be included.
Dietary fibers are classified according to several parameters,
including their primary food source, their chemical structure,
their water solubility and viscosity, and their fermentability.

Cell Host & Microbe 23, June 13, 2018 ª 2018 Elsevier Inc. 705

Dietary fibers are subdivided either into polysaccharides (non-
starch polysaccharides [NSPs], resistant starch [RS], and resis-
tant oligosaccharides [ROs]) or into insoluble and soluble forms
(Deehan et al., 2017). Most insoluble forms such as cellulose
and hemi-cellulose have a fecal bulking effect, as they reach
the colon and are not, or only slowly, digested by the gut bacte-
ria. Most soluble fibers do not contribute to fecal bulking, but are
fermented by the gut bacteria and thus give rise to metabolites
such as short-chain fatty acids (SCFAs). In contrast to ROs,
most soluble NSPs, especially polymers with high molecular
weight such as guar gum, certain pectins, b-glucans, and
psyllium, are viscous, meaning that they are able to form a gel
structure in the intestinal tract that can delay absorption of
glucose and lipids influencing post-prandial metabolism (Dee-
han et al., 2017).
Soluble and insoluble fibers are found in different food sources
such as legumes, vegetables, nuts, seeds, fruits, and cereals in
different proportions. However, not all types of fibers are present
in the same food categories. RS can only be found in starchy
foods such as cereals, legumes, tubers, and non-mature fruits
like green bananas, while pectins are more enriched in fruits
and some vegetables, whereas b-glucans and arabinoxylans
are present in cereals (Lovegrove et al., 2017). Although fibers
are present in a wide range of plant-based food sources, con-
sumption is low in Western countries. Fortification of foods
with extracted or synthesized non-digestible carbohydrates or
their use in dietary supplements therefore constitutes a strategy
to increase fiber intake. A wide range of these carbohydrate
polymers and oligosaccharides is commercially available (Dee-
han and Walter, 2016). Some of these compounds are consid-
ered ‘‘prebiotics’’ on the premise that they exert health benefits
by selectively inducing beneficial bacterial populations in the gut.
However, the assignment of only certain fibers as prebiotics
based on these criteria is somehow arbitrary (Bindels et al.,
2015; Deehan et al., 2017). As we describe in the following sec-
tions, virtually all fibers will induce specific shifts in microbiota
composition due to competitive interactions, and which of these
compositional shifts contribute to health benefits, or if they are
even functionally relevant, has not yet been established (Bindels
et al., 2015). In contrast, the mechanisms that have been demon-
strated to contribute to health benefits do not rely on a selective
utilization of the carbohydrate but rather on metabolic com-
pounds (e.g., SCFAs) (Koh et al., 2016), physiological changes
(pH lowering), or protection of the mucus layer (Schroeder
et al., 2018; Zou et al., 2018). Therefore, it may be worth consid-
ering a shift in focus of the prebiotic concept away from the
selective effect of specific dietary components on gut microbial
communities and instead toward ecological and functional con-
sequences of fiber fermentation, which is more relevant for host
physiology (Bindels et al., 2015).
Impact of Dietary Fiber on Microbial Ecology in the Gut
Diet has a major impact on gut microbiota composition, diversity,
and richness. Different components of the diet will shape the gut
bacterial communities in a time-dependent manner. Long-term
dietary patterns, particularly the intake of protein and animal fat
(Bacteroides) versus carbohydrates or plant-based foods (Prevo-
tella), are associated with so-called enterotypes (Wu et al., 2011).
This dichotomy in the Prevotella/Bacteroides ratio was also
706 Cell Host & Microbe 23, June 13, 2018
Cell Host & Microbe
Review
observed between industrialized and non-industrialized human
populations, suggesting that these bacterial populations are
driven by long-term differences in diet, e.g., meat (drives Bacter-
oides in the West) and dietary fiber (drives Prevotella in non-West-
ernized populations). Comparing gut microbiota of children from
rural (Burkina Faso [BF]) versus urban (Italy) communities
reflected the impact of diet on the microbiome. De Filippo et al.
found a significant difference within the gut microbiota composi-
tion in both groups after weaning. A significant increase in the
abundance of bacteria from the genera Prevotella and Xylani-
bacter associated with higher levels of fecal SCFAs was
observed in BF children, thus reflecting the ability of these individ-
uals to degrade complex carbohydrates (De Filippo et al., 2010).
These differences are independent of ethnicity as the gut bacte-
rial communities of BF children living in urban, as opposed to
rural, areas of BF became more similar to the Italian children.
When people move to urban areas, they are exposed to a West-
ernized lifestyle, including access to food rich in fat and simple
sugars. Accordingly, the microbiota of children living in the urban-
ized areas of BF have bacteria that are more suited to metabolize
animal protein, fat, and sugar-rich foods, while children living in
rural zones have a bacterial reservoir (enrichment in Prevotella,
Treponema, and Succinivibrio) adapted for fiber and carbohy-
drate fermentation from vegetables. Interestingly, the microbial
communities of BF children living in urban areas were compara-
ble to those of Italian children, highlighting the important impact
of the diet independent of host genetic (De Filippo et al., 2017).
These findings are supported by a study from Schnorr et al.
that showed that the Hadza hunter-gatherer individuals possess
higher levels of microbial richness and biodiversity compared to
Italian urban controls. The gut microbiota of these individuals
had increased Bacteroidetes and decreased Firmicutes abun-
dances, and unexpectedly they almost lack the Actinobacteria
phylum, including low levels of Bifidobacterium. Interestingly,
SCFA production in Hadza was characterized by increased
propionate concentrations, while the Italian cohort had more
butyrate (Schnorr et al., 2014). This segregation in SCFA produc-
tion may reflect differences in dietary variation related to the
amount and type of fiber and carbohydrates consumed by
both communities. Similarly, analysis of the microbiome of
Malawian, Venezuelan, and American populations from infants
to adults showed significant differences, which were associated
with diet and culture (Yatsunenko et al., 2012). The microbiome
of Malawian and Venezuelan infants was characterized by the
enrichment of bacterial genes implicated in vitamin B12 biosyn-
thesis, host glycan utilization, and urea catabolism, while
increased ability to metabolize fucose was observed in US
infants. In the same study, significant differences in microbial
functions between US versus Malawian and Venezuelan adults
were shown that corresponded to carnivorous (protein
consumption) versus herbivorous (dietary fiber consumption)
profiles, respectively.
Consistent with these observations, environmental lifestyle
changes rather than host genetics influence gut microbiota
diversity, and industrialization leads to a significant depletion of
species (Smits et al., 2017). The underlying mechanisms for
reduced diversity are proposed to include antibiotic utilization,
clinical practices (e.g., cesarean sections), and sanitation (Son-
nenburg and Sonnenburg, 2014). In agreement with this notion,
Cell Host & Microbe
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the most diverse microbiome to date is observed in the Yano-
mami, an indigenous population with limited contact to the
industrialized world (Clemente et al., 2015; Smits et al., 2017).
However, even in non-industrialized human populations with
access to antibiotics, such as rural Papua New Guineans, diver-
sity is higher than in the West (Martı́nez et al., 2015). Thus, other
environmental factors that differentiate Western and non-West-
ern human populations such as diet may be more important.
The non-Western populations consume far less refined diets
and significantly higher proportions of dietary fibers, suggesting
that this dietary component contributes to microbiota richness.
In fact, Sonnenburg et al. investigated the consequences of
the lack of fiber (referred to as MACs) intake in mice colonized
with a human microbiota and showed that a low-MAC diet led
to dramatically reduced microbial diversity in just three genera-
tions, which could not be restored when mice were moved to a
normal-MAC diet (Sonnenburg et al., 2016). Interestingly, they
also observed seasonal reductions in microbiome diversity in
Hadza hunter-gatherer individuals of Tanzania. The microbiota
composition and function of this community varied according
to seasonal changes and reflected dietary habit as well as the
type of food eaten (Smits et al., 2017). During the wet season,
the representation of CAZymes in the metagenome that are spe-
cific for plant carbohydrates was reduced and was associated
with a disappearance-reappearance cycle of specific OTUs
(operational taxonomic units) such as Prevotellaceae, which
are lost in industrialized populations. Similar seasonal observa-
tions were found in hibernating free-ranging brown bears in
which microbes associated with fiber utilization were increased
during the late spring and depleted during hibernation. The
enrichment of these bacteria led to increased efficiency in calorie
harvest from a fiber-rich diet (Sommer et al., 2016). Thus, peri-
odic reduction in fiber intake does not appear to have long-last-
ing effects on the microbiome (Smits et al., 2017), whereas long-
term reduction in fiber intake, like in the Western world, may lead
to permanent extinction of important microbial taxa, similar to
the findings in mice (Sonnenburg et al., 2016).
In addition to the long-term effects of the diet on the micro-
biome as outlined above, gut microbial communities respond
within 24 hr to dramatic changes in macronutrient composition
(David et al., 2014). In particular, taxa with fiber-degrading
capacity increased when humans were fed a plant-based diet.
In agreement, a dramatic and rapid rearrangement in the human
microbiome within 24 hr after reduction of carbohydrate
(including fiber) intake to 30 g/day was observed in a recent
human cohort study (Mardinoglu et al., 2018). As expected, the
loss in carbohydrates dramatically reduced the abundance of
fiber-degrading bacteria, while the abundance of Lactococcus,
Eggerrthella, and Streptococcus increased, resulting in reduced
levels of SCFAs (Mardinoglu et al., 2018).
Fiber Forms the Food Webs for Bacteria
Dietary administration of fiber alters the niche environment in the
gut by providing substrates for microbial growth, allowing micro-
bial species that are able to utilize these substrates to expand
their populations (Deehan et al., 2017). Together, the gut micro-
biome harbors 130 glycoside hydrolase, 22 polysaccharide
lyase, and 16 carbohydrate esterase families, which provide
the microbiome flexibility to switch between different energy
sources of fibers depending on availability (Flint et al., 2012).
Species belonging to Firmicutes and Actinobacteria are the
main responders to dietary fiber (Deehan et al., 2017), although
they contain relatively few fiber-metabolizing enzymes per
organism. However, they generally have more specialized roles
such as the initiation of complex substrate degradation. For
example, administration of RS has been shown to enrich Bifido-
bacterium adolescentis, Ruminoccocus bromii, Eubacterium
rectale, and Parabacteroides distasonis in a subset of individuals
dependent on RS (Martı́nez et al., 2010; Walker et al., 2011). In
contrast, the consumption of galactooligosaccharides mainly
induces Bifidobacterium species that possess the enzymatic
machinery to efficiently utilize this substrate (Davis et al.,
2011). It is not only the enzymatic capacity (as a primary fiber
degrader) that determines the ability of a microbe to benefit
from a dietary fiber, but also its ability to ‘‘adhere’’ to a substrate,
tolerate the environmental conditions changed through the fiber
(e.g., increased acidity through fermentation), and benefit from
carbohydrate breakdown products (secondary fiber degraders)
and metabolites (through cross-feeding) (Deehan et al., 2017).
Primary fiber degraders can hereby function as ‘‘keystone’’ spe-
cies that initiate the utilization of a complex fiber through what
can be considered a ‘‘guild’’ of species (Zhao et al., 2018). For
example, R. bromii is considered a keystone species for the
degradation of RS and contributes significantly to butyrate
production in the colon, although the species itself does not pro-
duce butyrate. Similar keystone species are likely to exist for
other dietary fiber types but have not yet been identified.
The impact of dietary fiber on microbiota composition displays
several consistent characteristics. First, the observed shifts
induced by non-digestible carbohydrates in humans, regardless
if they are accepted prebiotics or not, are restricted to a limited
number of taxa (Davis et al., 2011; Martı́nez et al., 2010; Walker
et al., 2011). Second, the magnitude of the induced changes can
be substantial, with specific species constituting more than 30%
of the total sequences obtained by amplicon sequencing of the
fecal microbiota (Davis et al., 2011; Martı́nez et al., 2010; Walker
et al., 2011). However, these changes are only maintained so
long as the substrate is consumed. Third, the microbial response
to dietary fiber is highly individualized (Davis et al., 2011; Martı́-
nez et al., 2010). The reason for this individuality is not yet under-
stood. Individuals may lack keystone species (Ze et al., 2012) or
lack strains that possess the enzymatic capacity to utilize a
specific substrate (Zhao et al., 2018).
Microbial Metabolism of Dietary Fibers and Functional
Implications
Dietary fibers are important energy sources for cecum and
colon-residing microbiota. Anaerobic bacteria under specific
intestinal conditions activate their machinery, constituted of
key enzymes and metabolic pathways, which can metabolize
complex carbohydrates, thus leading to the production of me-
tabolites such as SCFAs.
SCFAs are organic products mainly composed of acetate,
propionate, and butyrate. SCFAs possess key roles in regulating
host metabolism, immune system, and cell proliferation (Koh
et al., 2016). SCFAs are found at high concentration in the cecum
and proximal colon, where they are used as energy sources in
colonocytes (especially butyrate), but can also be transported
Cell Host & Microbe 23, June 13, 2018 707
 Cell Host & Microbe

Review
Figure 1. Effect of Low- and High-Fiber Diet
on Gut Microbiota Composition, Diversity,
Prudent Diet and Function in Host Physiology
Western Diet A diet rich in fiber contributes to the maintenance of
a healthy gut microbiota associated with increased
diversity and functions such as the production of
short-chain fatty acids (SCFAs). With the industri-
alization of the diet, low fiber intake, and high protein
and sugar consumption, the diversity of the gut
bacteria is reduced and their function is altered,
including significant reduction in their ability to
produce SCFAs, and associated with the appear-
High fat ance of chronic inflammatory diseases. High fiber
Phytochemicals Omega-3 fatty acids High sugar
intake and the production of SCFAs by the gut
Emulsifiers
bacteria enhance mucus and anti-microbial peptide
High dietary fiber, High meat protein production, and increase expression of tight junc-
MACs, Prebiotics Low dietary fiber tion proteins. In addition, SCFAs reduce oxygen
levels and maintain a functional immune system.
Toxic metabolites, Toxic
These biological processes are disrupted when the
SCFAs BCFAs bile acids diet is shifted toward a Western lifestyle and may
lead to increased susceptibility to infections and
Hyperglycemia
IBD, and to impaired physiology.

Enhanced mucus Increased antimicrobial Enhanced mucus Reduced antimicrobial

secretion peptides degradation peptides
CRC (Windey et al., 2012). Given the trade-
Lumen off between saccharolytic and proteolytic
fermentation, a high-fiber diet is likely to
inhibit protein fermentation counteracting
many of the detrimental effects of meat
Host
and fat, making these food components
Regulated immune response Proinflammatory immune response less detrimental.
upregulated downregulated
oxygen oxygen
tight junctions tight junctions
Effect of Dietary Fibers and SCFAs
Functional intestinal barrier on Host
Dysfunctional intestinal barrier

Immune Functional Dysfunctional Chronic

Mucus Production and Luminal
Health Inflammation
homeostasis barrier barrier disease Oxygen Levels
The gut epithelium is covered and pro-
Dietary fiber degrading Mucus degrading tected by a mucus layer, thus keeping
gut microbiota gut microbiota
bacteria separated from the mucosa
(Johansson et al., 2008). One of the
mechanisms used by the host to prevent
microbe invasions and susceptibility to
to the peripheral circulation via the portal vein to act on the liver infections is to maintain a well-structured and intact mucus
and peripheral tissues. Although the levels of SCFAs are low in layer. The gut microbiota and diet are two important compo-
the peripheral circulation, it is now well accepted that they act nents to maintain a normal structure and production of the
as signaling molecules and regulate different biological pro- intestinal mucus. An altered gut microbiota resulting from a
cesses in the host (Koh et al., 2016). diet low in fibers leads to a severe deterioration of the mucus
A low intake of dietary fiber does not only lead to reduced layer and can enhance the susceptibility to infections and the
microbial diversity and SCFA production, but also shifts the development of chronic inflammatory diseases (Figure 1) (De-
gut microbial metabolism toward the utilization of less favorable sai et al., 2016; Johansson et al., 2008; Schroeder et al.,
substrates, particularly dietary and endogenously supplied pro- 2018; Zou et al., 2018).
teins (Cummings and Macfarlane, 1991) and host mucins (Desai Dietary fibers and SCFAs stimulate mucus production and
et al., 2016; Schroeder et al., 2018; Zou et al., 2018), which may secretion. Both acetate and butyrate maintain a balance for
be detrimental to the host. Supplying human volunteers with a mucus production and secretion. Bacteroides thetaiotaomicron,
high-protein, low-carbohydrate diet did not only significantly an acetate and propionate producer, promotes goblet cell differ-
reduce the production of total SCFAs and butyrate (Duncan entiation and expression of mucin-related genes. In contrast,
et al., 2007), but also led to an increase in potentially detrimental Faecalibacterium prausnitzii, a consumer of acetate and a buty-
metabolites derived from the fermentation of amino acids, rate producer, reduces the effect of acetate on mucus and
including branched-chain fatty acids, ammonia, amines, N-ni- prevents overproduction of mucus, thus maintaining an appro-
troso compounds, phenolic compounds including p-Cresol, priate structure and composition of the gut epithelium (Wrzosek
sulphides, indolic compounds, and hydrogen sulfide. The et al., 2013). Furthermore, dietary fibers can also mechanically
cytotoxic and pro-inflammatory nature of these metabolites stimulate the intestinal epithelium to secrete mucus (McRorie
contributes to the development of chronic diseases, particularly and McKeown, 2017).

708 Cell Host & Microbe 23, June 13, 2018

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Prolonged lack of dietary fibers damages the mucus barrier
and is associated with increased abundance of mucin-degrad-
ing bacteria such as Akkermansia muciniphila (Desai et al.,
2016). Furthermore, when the diet is devoid of dietary fibers
some gut bacteria switch their metabolism to use mucin glycans
by inducing gene expression of mucin-degrading enzymes (Son-
nenburg et al., 2005). Consistent with this, Western-diet feeding
(very low fiber content) of mice increases the penetrability of the
inner mucus layer and lowers growth rate, rendering the mucus
penetrable, and may thus increase the susceptibility to infections
(Schroeder et al., 2018). Interestingly, low amount of inulin (1%),
a prebiotic with bifidogenic effect, or Bifidobacterium longum
administration prevented mucus defects. Inulin supplementation
corrected the penetrability of the inner mucus layer, while
B. longum supplementation restored the mucus growth rate
defect, suggesting that those two parameters are independent
and might be regulated by different factors. Neither 1% inulin
nor B. longum administration improved metabolic features of
obese animals. In contrast, high inulin intake (20%) prevented
microbiota encroachment, improved gut health, and led to a res-
olution of the low-grade inflammation associated with improve-
ment in metabolic parameters of obese mice (Zou et al., 2018).
Thus, it appears that although low levels of inulin are sufficient
for restoring local effects in the gut, including protection against
enteric infections (Desai et al., 2016), higher concentrations are
required for achieving metabolic benefits, suggesting separate
and dose-dependent mechanisms. However, such high doses
of inulin would most likely not be tolerated in humans (Figure 1).
An important recent discovery from the Ba €umler lab demon-
strated that beta-oxidation of butyrate by colonocytes con-
sumes oxygen and results in an anaerobic milieu in the gut
(Byndloss et al., 2017). Since butyrate-producing bacteria are
very sensitive to oxygen, their abundance is reduced further,
lowering the amount of butyrate production. This feedforward
loop results in increased luminal oxygen levels, allowing Proteo-
bacteria such as Escherichia coli and S. enterica serovar Typhi-
murium to bloom. This novel mechanism provides not only an
explanation for many of the pathologies associated with a low-fi-
ber diet, but also a mechanistic understanding for why reduced
microbial diversity is observed in both humans and mice on a
low-fiber diet.
The Immune System
A healthy gut microbiota contributes to the maturation and the
development of the immune system (Rescigno, 2014). One
such mechanism is through SCFAs, which are known to promote
generation of colonic regulatory T cells (Tregs) in a GPR43-
dependent manner as well as by inducing histone H3 acetylation
(Furusawa et al., 2013; Smith et al., 2013). Accordingly, maternal
high-fiber feeding during pregnancy and lactation modulate
thymic microenvironment and induced autoimmune regulator
(Aire) expression, a factor expressed in the thymus, a primary
lymphoid tissue, which is essential for the maturation of T cells.
The maternal fiber intake increased butyrate levels in the blood
of the offspring and contributed to the enhancement of peripheral
and thymic Treg counts of the animals in a GPR41-dependent
manner (Nakajima et al., 2017). In contrast, high-fat diet induces
premature thymic involution reflected by the reduced thymocyte
counts and the increased apoptosis of developing T cell popula-
tions (Yang et al., 2009). These phenotypes may help explain why
obese people have accelerated thymic aging and alteration of
primary lymphoid tissue architecture (Andersen et al., 2016).
Taken together, these observations emphasize the important
role of SCFAs in regulating and maintaining a normal function
of the innate and adaptive immune system, and although we
have limited the discussion to a few examples, there are several
links between fiber intake, immune system, and diseases as
illustrated below (Figure 1).
The Local Beneficial Effect of Fiber Intake
IBD and CRC
The incidence of IBD is increasing in occidental countries, and
the Westernization of the diet and lower gut bacterial diversity,
especially reduction in butyrate-producing bacteria, have been
suggested to contribute to increased IBD prevalence (Ott and
Schreiber, 2006). In agreement, low fiber intake is correlated
with increased incidence of Crohn’s disease (Hou et al., 2011)
and exacerbates colitis in mice. By investigating the effect of
40 defined diets in mice, Llewellyn et al. demonstrated that
dietary protein and fibers had negative and beneficial effects
on colitis development, respectively. Similarly, mice developed
DSS-induced colitis proportional to the amount of fibers in the
diet (Macia et al., 2015). The preventive effect of fibers may be
due to increased cecal SCFA levels, especially butyrate, which
is known to have anti-inflammatory properties, potentially
through GPR43 (Maslowski et al., 2009).
IBD can lead to CRC (Beaugerie and Itzkowitz, 2015), which is
the third most common cancer (Johnson et al., 2013). CRC is
associated with genetic and environmental factors such as die-
tary habits, smoking, and physical activity (Johnson et al.,
2013), and butyrate-producing bacteria are reduced in CRC
patients compared to healthy volunteers (Wang et al., 2012).
Reduced dietary fiber intake is associated with increased inci-
dence of CRC (Aune et al., 2016). Thus, it is not surprising that
diets low in fat and high in fiber-containing grain products, veg-
etables, and fruits have health claims, approved by the FDA, for a
potential reduction of the incidence of developing some types of
cancer. In agreement, a dietary intervention increasing dietary
fibers in African Americans changed the microbiome and
increased butyrogenesis, resulting in reduction of biomarkers
of cancer risk (O’Keefe et al., 2015).
The Systemic Beneficial Effect of Fiber Intake
Lung COPD and Asthma
Fiber intake and SCFAs not only act locally but can also affect
lung physiology. Patients suffering from severe persistent
asthma consumed more fat and less fiber compared with healthy
controls (Berthon et al., 2013). Similarly, a prospective study
showed an inverse relationship between cereal fiber intake and
the risk of chronic obstructive pulmonary disease (COPD) (Raffa-
tellu et al., 2008). In mice, prolonged low-fiber feeding aggra-
vated allergic airway disease in mice (Trompette et al., 2014),
which could be corrected by administration of the SCFA propio-
nate (Trompette et al., 2014). Thus, it appears that the increase in
different airway disease may be coupled to microbial fermenta-
tion of dietary fibers.
Obesity and Diabetes
The epidemic of obesity is occurring in both developing and
industrialized countries. Obesity is influenced by several factors
Cell Host & Microbe 23, June 13, 2018 709

such as specific dietary and lifestyle behaviors and is associated
with reduced microbial diversity, which may reflect reduced fiber
intake. In agreement, a prospective study on 120,877 non-obese
individuals demonstrated that long-term weight gain was
inversely correlated with intake of dietary fibers, suggesting their
role in limiting long-term body weight gain (Mozaffarian et al.,
2011). Similarly, high fiber intake is associated with increased
gut microbial diversity and lower long-term weight gain (Menni
et al., 2017). A recent intervention study with oligofructose-
enriched inulin for 16 weeks in overweight and obese children
reduced their fat mass, suggesting that increased intake of
fermentable fibers may have beneficial effects on obesity (Nico-
lucci et al., 2017).
Obesity is associated with type 2 diabetes (T2D). In contrast to
obesity, T2D is associated with reduced abundance of fiber-de-
grading bacteria (Karlsson et al., 2013; Qin et al., 2012). Accord-
ingly, diets with high glucose index (high in digestible starch and
low in fiber) are associated with an increased diabetes risk (Sluijs
et al., 2012). Administration of soluble fibers, such as oligofruc-
tose and long-chain inulin, corrected gut dysbiosis, reduced
body weight gain and low-grade inflammation, and improved
glucose metabolism, which was at least attributed to decreased
intestinal permeability and endotoxemia (Cani et al., 2007, 2008).
Furthermore, providing healthy human volunteers with barley
kernel-based bread (BKB), rich in b-glucans, improved glucose
metabolism (Nilsson et al., 2015). Thus, it is tempting to specu-
late that whereas the reduced diversity in obesity is caused by
reduced fiber intake, lack of fiber-degrading and butyrate-pro-
ducing bacteria may predispose to T2D.
SCFA-Independent Effect of Dietary Fibers
Thus far, this review has focused mainly on the fermentation of
fibers to SCFAs, but it is important to mention that microbial
metabolism of fibers also has additional effects. Ferulic acid
(FA) is a phenolic compound that can be found in plant cell
wall and serves to enhance its rigidity and strength. Microbial
metabolism of dietary fibers, for example those found in cereal
bran, leads to the release of FA by bacteria such as
L. fermentum NCIMB 5221 harboring the FA esterase gene
(Tomaro-Duchesneau et al., 2012). In the digestive tract, FA
can either act locally to modulate gut physiology or be trans-
ported in its free form into the bloodstream to influence systemic
health. FA has antioxidant and anti-inflammatory properties and
could be considered as a potential therapeutic treatment for
various chronic pathologies such as neurodegeneration, obesity,
diabetes, and cancer. FA administration stimulates neurogene-
sis in corticosterone-treated mice and was shown to prevent
Ab-related toxicity in Alzheimer disease models (Mori et al.,
2013). In a model of ulcerative colitis, FA treatment showed
anti-inflammatory properties reflected by the reduction of pro-in-
flammatory cytokine and the upregulation of IL-10 (Sadar et al.,
2016). In addition, FA can prevent development of diet-induced
obesity (de Melo et al., 2017) and has anti-diabetic effects: dia-
betic rats treated with this compound normalized glucose and
serum insulin levels (Narasimhan et al., 2015).
Dietary fibers can also bind different micro- and macronutri-
ents including ions such as copper, calcium, and zinc and trans-
port them to the distal gut, where they are released when the
fiber is metabolized by the colonic bacteria (Bergman et al.,
710 Cell Host & Microbe 23, June 13, 2018
Cell Host & Microbe
Review
1997). Acidification through the production of SCFAs further
increases mineral solubility and absorption by the colon (Baye
et al., 2017; Trinidad et al., 1997). Some of these ions possess
anti-microbial action under specific conditions and help in the
prevention from gut infections. Thus, we hypothesize that the
capacity of different dietary fibers to bind ions in the gut may
serve to establish important local reservoirs. Accordingly, zinc
has been shown to promote the metabolic activity of gut micro-
biota of weaned piglets (Højberg et al., 2005), resulting in
improved metabolic health parameters. In parallel, a recent
study in chickens demonstrated that zinc-deficient diet results
in lower gut microbiota diversity associated with reduced
SCFA production (Reed et al., 2015). These observations sug-
gest that dietary fibers could participate in preserving a healthy
intestinal ecology by providing micronutrients to bacteria and
the host in the distal gut. However, some studies suggested
that mineral binding to dietary fibers may lower their availability
for the host, which may lead to mineral deficiency (Baye et al.,
2017). It is thus important to determine the mineral binding
capacity and effects on homeostasis for different fibers.
In addition to regulating bioavailability to nutrients as sug-
gested above, fibers may also form platforms for bringing bacte-
ria and biomolecules into close proximity. For example, conju-
gated bile acids in the small intestine can bind to fibers before
they are deconjugated by Bacteroides and Lacotobacillus
species (Kahlon and Woodruff, 2003). Deconjugation is a prereq-
uisite for further biotransformation to secondary bile acids by low
abundant bacteria such as Clostridium scindens (Reddy et al.,
1992). We thus suggest that binding of both bile acids and spe-
cific bacteria to the same fiber, which serves as a platform, can
explain how low abundant bacteria can serve as efficient trans-
formers of biomolecules and thus increase production of
secondary bile acids. Secondary bile acids, such as deoxycholic
acids, have a number of physiologically important effects and
have been positively associated with both CRC (Bernstein
et al., 2005) and improved metabolism (Li and Chiang, 2015)
(Figure 2). This platform concept can perhaps be extended to
additional bacteria and biomolecules.
One Size Does Not Fit All: Fiber Quantity and
Personalization
The role of dietary fibers in preventing and alleviating chronic
inflammatory diseases in humans has been widely studied
during the past years, although findings from intervention trials
are often inconsistent (Buyken et al., 2014). Studies performed
on animal models usually have more dramatic effects, but also
use higher amount of fibers compared to levels used in human
clinical trials, especially for prebiotics, whose dose is often
40-fold higher on a body weight basis (Schaafsma and Slavin,
2014). In fact, the dose of dietary fiber used in animal studies
more closely resembles the estimated amount of fiber
consumed by our ancestors before the advent of agriculture
(>100 g/day) (Eaton et al., 1997). Therefore, even fiber doses
that meet the dietary recommendations of today (30 g/day)
(Jones, 2014) are still far below the fiber amounts ingested
when the symbiosis between us and the microbes was formed
(Deehan and Walter, 2016). Non-industrialized human popula-
tions that consume fiber amounts of more than 50 g/day, such
as rural South Africans and rural Ugandans, are known to be
Cell Host & Microbe

Review
Figure 2. SCFA-Independent Effect of Dietary
Fibers in Colon
Dietary fibers bind conjugated primary bile acids
BSH 7α-dehydroxylation Gut bacteria (BAs) and may serve as a platform for gut bacteria
that possess the bile salt hydrolase (Bsh), leading to
the production of non-conjugated BAs. These can
also bind to dietary fibers and be further metabolized
by specific bacteria with 7-alpha dehydroxylation
activity, thus generating secondary BAs. The fact
that dietary fibers can bind secondary BAs suggests
that they may play a role in regulating BA levels
within the gut. This structural interaction may
modulate host physiology either by preventing the
accumulation of toxic BAs that can lead to the
development of polyps and colorectal cancer (CRC)
or by increasing the disposal of BAs that can acti-
Increased colonic vate TGR5 to increase glucagon-like peptide 1
absorption (GLP-1) secretion. In addition, bacterial degradation
of dietary fibers leads to the release of minerals and
phenolic compounds, which can be absorbed by the
distal gut.

Colon polyps can lead to undesirable side effects, such

as flatulence, bloating, stomachaches,
diarrhea, and constipation (Grabitske
and Slavin, 2009), and may thus be nega-
Increased tive for individuals with irritable bowel syn-
GLP-1 colonic excretion Polyp formation
drome. In addition, a few recent studies
using animal models suggest that fiber
intake and/or their derived metabolites
may have a negative impact on host
Conjugated Phenolic compounds health in specific conditions such as coli-
primary bile acids tis (Miles et al., 2017) and/or CRC (Bel-
Minerals and ions cheva et al., 2014). Although the over-
Unconjugated whelming data suggest beneficial effects
primary bile acids Carbohydrate of fibers, there may be instances in which
binding protein caution in making generalizable recom-
Secondary mendations is warranted. It should be
bile acids TGR5 noted that tolerance to fiber is dependent
on the individual and often improves over
time as the gastrointestinal tract and mi-
crobiota adapt to higher doses of dietary
fiber (Mego et al., 2017). It is therefore
largely free from chronic inflammatory diseases. Most impor- realistic to have the diet of modern humans enriched with fiber
tantly, moving African Americans to an ‘‘African-style’’ diet with beyond 50 g daily, especially with sufficient acclimatization and
55 g fiber reversed risk markers of CRC within only 2 weeks if slower fermenting polysaccharides, such as RS, arabinoxy-
(O’Keefe et al., 2015). Therefore, it is plausible that dietary fiber lan, acacia gum, and resistant maltodextrin, are consumed
supplementation below these doses, which are used in virtually since these fiber types are better tolerated at higher doses
all human intervention trials today, are too low and physiologi- than faster fermenting oligosaccharides like oligofructose or
cally irrelevant. Recent suggestions postulate daily fiber galactooligosaccharides (Deehan and Walter, 2016). For future
amounts of greater than 50 g to achieve health benefits linked applications, one could use specific fiber types in a personal-
to fiber (Deehan et al., 2017; O’Keefe, 2018), and accordingly, ized fashion (matched with microbiota profile) to reduce the
human interventions with greater than 50 g/day of fiber observed severity of side effects while enhancing the physiologic benefit
significant improvements in the assessed health markers (Jen- to the host.
kins et al., 2001; O’Keefe et al., 2015; Pedersen et al., 2013; Inconsistencies in human intervention trials could also result
Zhao et al., 2018). However, high fiber amounts will be chal- from the response of the human gut microbiota to dietary fiber
lenging to achieve with regular food items but could be achieved being highly individualized (Davis et al., 2011; Martı́nez et al.,
by systematically supplementing the food supply with dietary 2010). Missing keystone species in individuals, the absence of
fiber sources (Deehan and Walter, 2016). functional ‘‘guilds’’ able to assess a fiber, and/or the absence
There are concerns, however, that modern humans may of strains that can utilize specific fiber sources could explain
have problems tolerating such high doses of fiber as its intake why some studies show segregation in response profiles of

Cell Host & Microbe 23, June 13, 2018 711


patients during dietary intervention (Deehan et al., 2017). Match-
ing of fibers to the microbiota may produce more beneficial ef-
fects on the host, especially if the subject’s lack of keystone spe-
cies leads to a non-response profile. This was exemplified in a
recent study showing that supplementation of BKB did not result
in metabolic improvement in all healthy subjects. Individuals who
exhibited improved metabolic profile after 3 days of BKB con-
sumption had a higher Prevotella/Bacteriodes ratio with an
enrichment of Prevotella copri, reflecting the ability to degrade
complex carbohydrates (Kovatcheva-Datchary et al., 2015).
Interestingly, the capacity for using fibers varies between Prevo-
tella- versus Bacteroides-dominated gut microbiota. Prevotella-
dominated bacteria produce higher levels and different propor-
tions of SCFAs compared to Bacteroides-dominated microbiota
(Chen et al., 2017). In parallel, a very elegant study performed on
800 individuals, representative of an adult non-prediabetic
population, showed that post-prandial glucose response
(PPGR) was highly variable between individuals who consumed
the same standardized meal. The PPGR correlated with some
microbiota features, highlighting the importance of the diet-mi-
crobiota interaction and its impact on host metabolism. An
algorithm using clinical and microbiota profiles as input demon-
strated that the PPGR of each individual can be predicted and
that a personalized dietary intervention based on their predictor
can lead to an improvement in glucose metabolism including
lower PPGR (Zeevi et al., 2015).
Concluding Remarks
In conclusion, dietary fibers can be considered key ancestral
compounds that preserve gut ecology, especially regulating
macronutrients and host physiology. Screening novel fibers,
both extracted and purified from food as well as those selectively
modified or synthesized, for their potential as the next-genera-
tion prebiotics, and defining efficient strategies to reintroduce
high amount of fibers aiming at replenishing the gut microbiome
with essential missing microbes, will be the next challenge to
significantly impact gut microbiota-associated human diseases.
Finally, a better understanding of diet-microbiota interactions
will help to develop a personalized nutrition approach that would
target and reduce more efficiently the incidence of chronic in-
flammatory diseases.
ACKNOWLEDGMENTS
We are grateful to Anna Hallén for producing the figures. This study was sup-
ported by the Novo Nordisk Foundation, the Swedish Research Council, the
Swedish Diabetes Foundation, the Swedish Heart Lung Foundation, Göran
Gustafsson’s Foundation, Knut and Alice Wallenberg Foundation, the FP7-
sponsored program METACARDIS, JPI (healthy diet for a healthy life), the
regional agreement on medical training and clinical research (ALF) between
Region Va €stra Götaland and Sahlgrenska University Hospital, and a grant
from a Transatlantic Networks of Excellence Award from the Leducq Founda-
tion. F.B. is Torsten Söderberg Professor in Medicine and recipient of an ERC
Consolidator Grant (European Research Council, Consolidator grant 615362 -
METABASE). J.W. is a Campus Alberta Innovation Program (CAIP) chair for
Nutrition, Microbes, and Gastrointestinal Health and recipient of grants from
the Canadian Institutes of Health Research (CIHR) and JPI (healthy diet for a
healthy life).
DECLARATION OF INTERESTS
J.W. has received research funding from industry sources involved in the
manufacture and marketing of prebiotics and dietary fibers, and is a co-owner
712 Cell Host & Microbe 23, June 13, 2018
Cell Host & Microbe
Review
of Synbiotics Solutions, a developer of synbiotic products. F.B. is founder and
shareholder of Metabogen AB.
REFERENCES
Andersen, C.J., Murphy, K.E., and Fernandez, M.L. (2016). Impact of obesity
and metabolic syndrome on immunity. Adv. Nutr. 7, 66–75.
Aune, D., Keum, N., Giovannucci, E., Fadnes, L.T., Boffetta, P., Greenwood,
D.C., Tonstad, S., Vatten, L.J., Riboli, E., and Norat, T. (2016). Whole grain con-
sumption and risk of cardiovascular disease, cancer, and all cause and cause
specific mortality: systematic review and dose-response meta-analysis of pro-
spective studies. BMJ 353, i2716.
Ba€ckhed, F., Ding, H., Wang, T., Hooper, L.V., Koh, G.Y., Nagy, A., Semenko-
vich, C.F., and Gordon, J.I. (2004). The gut microbiota as an environmental
factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 101, 15718–15723.
Baye, K., Guyot, J.P., and Mouquet-Rivier, C. (2017). The unresolved role of
dietary fibers on mineral absorption. Crit. Rev. Food Sci. Nutr. 57, 949–957.
Beaugerie, L., and Itzkowitz, S.H. (2015). Cancers complicating inflammatory
bowel disease. N. Engl. J. Med. 373, 195.
Belcheva, A., Irrazabal, T., Robertson, S.J., Streutker, C., Maughan, H., Ru-
bino, S., Moriyama, E.H., Copeland, J.K., Surendra, A., Kumar, S., et al.
(2014). Gut microbial metabolism drives transformation of MSH2-deficient
colon epithelial cells. Cell 158, 288–299.
Bergman, C.J., Gualberto, D.G., and Weber, C.W. (1997). Mineral binding ca-
pacity of dephytinized insoluble fiber from extruded wheat, oat and rice brans.
Plant Foods Hum. Nutr. 51, 295–310.
Bernstein, H., Bernstein, C., Payne, C.M., Dvorakova, K., and Garewal, H.
(2005). Bile acids as carcinogens in human gastrointestinal cancers. Mutat.
Res. 589, 47–65.
Berthon, B.S., Macdonald-Wicks, L.K., Gibson, P.G., and Wood, L.G. (2013).
Investigation of the association between dietary intake, disease severity and
airway inflammation in asthma. Respirology 18, 447–454.
Bindels, L.B., Delzenne, N.M., Cani, P.D., and Walter, J. (2015). Towards a
more comprehensive concept for prebiotics. Nat. Rev. Gastroenterol. Hepatol.
12, 303–310.
Buyken, A.E., Goletzke, J., Joslowski, G., Felbick, A., Cheng, G., Herder, C.,
and Brand-Miller, J.C. (2014). Association between carbohydrate quality and
inflammatory markers: systematic review of observational and interventional
studies. Am. J. Clin. Nutr. 99, 813–833.
Byndloss, M.X., Olsan, E.E., Rivera-Chávez, F., Tiffany, C.R., Cevallos, S.A.,
Lokken, K.L., Torres, T.P., Byndloss, A.J., Faber, F., Gao, Y., et al. (2017).
Microbiota-activated PPAR-g signaling inhibits dysbiotic Enterobacteriaceae
expansion. Science 357, 570–575.
Cani, P.D., Neyrinck, A.M., Fava, F., Knauf, C., Burcelin, R.G., Tuohy, K.M.,
Gibson, G.R., and Delzenne, N.M. (2007). Selective increases of bifidobac-
teria in gut microflora improve high-fat-diet-induced diabetes in mice
through a mechanism associated with endotoxaemia. Diabetologia 50,
2374–2383.
Cani, P.D., Bibiloni, R., Knauf, C., Waget, A., Neyrinck, A.M., Delzenne, N.M.,
and Burcelin, R. (2008). Changes in gut microbiota control metabolic endotox-
emia-induced inflammation in high-fat diet-induced obesity and diabetes in
mice. Diabetes 57, 1470–1481.
Chen, T., Long, W., Zhang, C., Liu, S., Zhao, L., and Hamaker, B.R. (2017). Fi-
ber-utilizing capacity varies in Prevotella- versus Bacteroides-dominated gut
microbiota. Sci. Rep. 7, 2594.
Clemente, J.C., Pehrsson, E.C., Blaser, M.J., Sandhu, K., Gao, Z., Wang, B.,
Magris, M., Hidalgo, G., Contreras, M., Noya-Alarcón, Ó., et al. (2015). The
microbiome of uncontacted Amerindians. Sci. Adv. 1, e1500183.
Cummings, J.H., and Macfarlane, G.T. (1991). The control and consequences
of bacterial fermentation in the human colon. J. Appl. Bacteriol. 70, 443–459.
David, L.A., Maurice, C.F., Carmody, R.N., Gootenberg, D.B., Button, J.E.,
Wolfe, B.E., Ling, A.V., Devlin, A.S., Varma, Y., Fischbach, M.A., et al.
(2014). Diet rapidly and reproducibly alters the human gut microbiome. Nature
505, 559–563.
Cell Host & Microbe
Review
Davis, L.M., Martı́nez, I., Walter, J., Goin, C., and Hutkins, R.W. (2011). Bar-
coded pyrosequencing reveals that consumption of galactooligosaccharides
results in a highly specific bifidogenic response in humans. PLoS One 6,
e25200.
De Filippo, C., Cavalieri, D., Di Paola, M., Ramazzotti, M., Poullet, J.B., Mas-
sart, S., Collini, S., Pieraccini, G., and Lionetti, P. (2010). Impact of diet in
shaping gut microbiota revealed by a comparative study in children from
Europe and rural Africa. Proc. Natl. Acad. Sci. USA 107, 14691–14696.
De Filippo, C., Di Paola, M., Ramazzotti, M., Albanese, D., Pieraccini, G.,
Banci, E., Miglietta, F., Cavalieri, D., and Lionetti, P. (2017). Diet, environments,
and gut microbiota. a preliminary investigation in children living in rural and
urban Burkina Faso and Italy. Front. Microbiol. 8, 1979.
de Melo, T.S., Lima, P.R., Carvalho, K.M., Fontenele, T.M., Solon, F.R., Tomé,
A.R., de Lemos, T.L., da Cruz Fonseca, S.G., Santos, F.A., Rao, V.S., and de
Queiroz, M.G. (2017). Ferulic acid lowers body weight and visceral fat accumu-
lation via modulation of enzymatic, hormonal and inflammatory changes in a
mouse model of high-fat diet-induced obesity. Braz. J. Med. Biol. Res.
50, e5630.
Deehan, E.C., and Walter, J. (2016). The fiber gap and the disappearing gut mi-
crobiome: implications for human nutrition. Trends Endocrinol. Metab. 27,
239–242.
Deehan, E.C., Duar, R.M., Armet, A.M., Perez-Muñoz, M.E., Jin, M., and Wal-
ter, J. (2017). Modulation of the gastrointestinal microbiome with nondigestible
fermentable carbohydrates to improve human health. Microbiol. Spectr. 5,
https://doi.org/10.1128/microbiolspec.BAD-0019-2017.
Desai, M.S., Seekatz, A.M., Koropatkin, N.M., Kamada, N., Hickey, C.A., Wol-
ter, M., Pudlo, N.A., Kitamoto, S., Terrapon, N., Muller, A., et al. (2016). A
dietary fiber-deprived gut microbiota degrades the colonic mucus barrier
and enhances pathogen susceptibility. Cell 167, 1339–1353.e21.
Duncan, S.H., Belenguer, A., Holtrop, G., Johnstone, A.M., Flint, H.J., and Lob-
ley, G.E. (2007). Reduced dietary intake of carbohydrates by obese subjects
results in decreased concentrations of butyrate and butyrate-producing
bacteria in feces. Appl. Environ. Microbiol. 73, 1073–1078.
Eaton, S.B., Eaton, S.B., 3rd, and Konner, M.J. (1997). Paleolithic nutrition re-
visited: a twelve-year retrospective on its nature and implications. Eur. J. Clin.
Nutr. 51, 207–216.
Flint, H.J., Scott, K.P., Duncan, S.H., Louis, P., and Forano, E. (2012). Microbial
degradation of complex carbohydrates in the gut. Gut Microbes 3, 289–306.
Furusawa, Y., Obata, Y., Fukuda, S., Endo, T.A., Nakato, G., Takahashi, D.,
Nakanishi, Y., Uetake, C., Kato, K., Kato, T., et al. (2013). Commensal
microbe-derived butyrate induces the differentiation of colonic regulatory
T cells. Nature 504, 446–450.
Grabitske, H.A., and Slavin, J.L. (2009). Gastrointestinal effects of low-digest-
ible carbohydrates. Crit. Rev. Food Sci. Nutr. 49, 327–360.
Hand, T.W., Vujkovic-Cvijin, I., Ridaura, V.K., and Belkaid, Y. (2016). Linking
the microbiota, chronic disease, and the immune system. Trends Endocrinol.
Metab. 27, 831–843.
Højberg, O., Canibe, N., Poulsen, H.D., Hedemann, M.S., and Jensen, B.B.
(2005). Influence of dietary zinc oxide and copper sulfate on the gastrointes-
tinal ecosystem in newly weaned piglets. Appl. Environ. Microbiol. 71,
2267–2277.
Hou, J.K., Abraham, B., and El-Serag, H. (2011). Dietary intake and risk of
developing inflammatory bowel disease: a systematic review of the literature.
Am. J. Gastroenterol. 106, 563–573.
Jenkins, D.J., Kendall, C.W., Popovich, D.G., Vidgen, E., Mehling, C.C., Vuk-
san, V., Ransom, T.P., Rao, A.V., Rosenberg-Zand, R., Tariq, N., et al.
(2001). Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids
and colonic function. Metabolism 50, 494–503.
Johansson, M.E., Phillipson, M., Petersson, J., Velcich, A., Holm, L., and Hans-
son, G.C. (2008). The inner of the two Muc2 mucin-dependent mucus layers in
colon is devoid of bacteria. Proc. Natl. Acad. Sci. USA 105, 15064–15069.
Johnson, C.M., Wei, C., Ensor, J.E., Smolenski, D.J., Amos, C.I., Levin, B., and
Berry, D.A. (2013). Meta-analyses of colorectal cancer risk factors. Cancer
Causes Control 24, 1207–1222.
Jones, J.M. (2014). CODEX-aligned dietary fiber definitions help to bridge the
‘fiber gap’. Nutr. J. 13, 34.
Kahlon, T.S., and Woodruff, C.L. (2003). In vitro binding of bile acids by rice
bran, oat bran, barley and b-glucan enriched barley. Cereal Chem. 80,
260–263.
Karlsson, F.H., Tremaroli, V., Nookaew, I., Bergström, G., Behre, C.J., Fager-
€ckhed, F. (2013). Gut metagenome in European
berg, B., Nielsen, J., and Ba
women with normal, impaired and diabetic glucose control. Nature
498, 99–103.
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., and Ba €ckhed, F. (2016).
From dietary fiber to host physiology: short-chain fatty acids as key bacterial
metabolites. Cell 165, 1332–1345.
Kovatcheva-Datchary, P., Nilsson, A., Akrami, R., Lee, Y.S., De Vadder, F., Ar-
€ckhed, F. (2015). Dietary fiber-
ora, T., Hallen, A., Martens, E., Björck, I., and Ba
induced improvement in glucose metabolism is associated with increased
abundance of Prevotella. Cell Metab. 22, 971–982.
Li, T., and Chiang, J.Y. (2015). Bile acids as metabolic regulators. Curr. Opin.
Gastroenterol. 31, 159–165.
Logan, A.C., Jacka, F.N., and Prescott, S.L. (2016). Immune-microbiota inter-
actions: dysbiosis as a global health issue. Curr. Allergy Asthma Rep. 16, 13.
Lovegrove, A., Edwards, C.H., De Noni, I., Patel, H., El, S.N., Grassby, T.,
Zielke, C., Ulmius, M., Nilsson, L., Butterworth, P.J., et al. (2017). Role of poly-
saccharides in food, digestion, and health. Crit. Rev. Food Sci. Nutr. 57,
237–253.
Macia, L., Tan, J., Vieira, A.T., Leach, K., Stanley, D., Luong, S., Maruya, M.,
Ian McKenzie, C., Hijikata, A., Wong, C., et al. (2015). Metabolite-sensing re-
ceptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis
through regulation of the inflammasome. Nat. Commun. 6, 6734.
€ sa
€nen,
Mardinoglu, A., Wu, H., Bjornson, E., Zhang, C., Hakkarainen, A., Ra
€inen, K.H., et al. (2018).
S.M., Lee, S., Mancina, R.M., Bergentall, M., Pietila
An integrated understanding of the rapid metabolic benefits of a carbohy-
drate-restricted diet on hepatic steatosis in humans. Cell Metab. 27,
559–571.e5.
Martı́nez, I., Kim, J., Duffy, P.R., Schlegel, V.L., and Walter, J. (2010). Resistant
starches types 2 and 4 have differential effects on the composition of the fecal
microbiota in human subjects. PLoS One 5, e15046.
Martı́nez, I., Stegen, J.C., Maldonado-Gómez, M.X., Eren, A.M., Siba, P.M.,
Greenhill, A.R., and Walter, J. (2015). The gut microbiota of rural papua new
guineans: composition, diversity patterns, and ecological processes. Cell
Rep. 11, 527–538.
Maslowski, K.M., Vieira, A.T., Ng, A., Kranich, J., Sierro, F., Yu, D., Schilter,
H.C., Rolph, M.S., Mackay, F., Artis, D., et al. (2009). Regulation of inflamma-
tory responses by gut microbiota and chemoattractant receptor GPR43.
Nature 461, 1282–1286.
McRorie, J.W., Jr., and McKeown, N.M. (2017). Understanding the physics of
functional fibers in the gastrointestinal tract: an evidence-based approach to
resolving enduring misconceptions about insoluble and soluble fiber.
J. Acad. Nutr. Diet. 117, 251–264.
Mego, M., Accarino, A., Tzortzis, G., Vulevic, J., Gibson, G., Guarner, F., and
Azpiroz, F. (2017). Colonic gas homeostasis: Mechanisms of adaptation
following HOST-G904 galactooligosaccharide use in humans. Neurogastroen-
terol. Motil. 29, https://doi.org/10.1111/nmo.13080.
Menni, C., Jackson, M.A., Pallister, T., Steves, C.J., Spector, T.D., and Valdes,
A.M. (2017). Gut microbiome diversity and high-fibre intake are related to lower
long-term weight gain. Int. J. Obes. 41, 1099–1105.
Miles, J.P., Zou, J., Kumar, M.V., Pellizzon, M., Ulman, E., Ricci, M., Gewirtz,
A.T., and Chassaing, B. (2017). Supplementation of low- and high-fat diets with
fermentable fiber exacerbates severity of DSS-induced acute colitis. Inflamm.
Bowel Dis. 23, 1133–1143.
Mori, T., Koyama, N., Guillot-Sestier, M.V., Tan, J., and Town, T. (2013).
Ferulic acid is a nutraceutical b-secretase modulator that improves behavioral
impairment and alzheimer-like pathology in transgenic mice. PLoS One 8,
e55774.
Cell Host & Microbe 23, June 13, 2018 713

Mozaffarian, D., Hao, T., Rimm, E.B., Willett, W.C., and Hu, F.B. (2011).
Changes in diet and lifestyle and long-term weight gain in women and men.
N. Engl. J. Med. 364, 2392–2404.
Nakajima, A., Kaga, N., Nakanishi, Y., Ohno, H., Miyamoto, J., Kimura, I., Hori,
S., Sasaki, T., Hiramatsu, K., Okumura, K., et al. (2017). Maternal high fiber diet
during pregnancy and lactation influences regulatory T cell differentiation in
offspring in mice. J. Immunol. 199, 3516–3524.
Narasimhan, A., Chinnaiyan, M., and Karundevi, B. (2015). Ferulic acid exerts
its antidiabetic effect by modulating insulin-signalling molecules in the liver of
high-fat diet and fructose-induced type-2 diabetic adult male rat. Appl. Phys-
iol. Nutr. Metab. 40, 769–781.
Nicolucci, A.C., Hume, M.P., Martı́nez, I., Mayengbam, S., Walter, J., and Re-
imer, R.A. (2017). Prebiotics reduce body fat and alter intestinal microbiota in
children who are overweight or with obesity. Gastroenterology 153, 711–722.
Nilsson, A.C., Johansson-Boll, E.V., and Björck, I.M. (2015). Increased gut hor-
mones and insulin sensitivity index following a 3-d intervention with a barley
kernel-based product: a randomised cross-over study in healthy middle-
aged subjects. Br. J. Nutr. 114, 899–907.
O’Keefe, S.J.D. (2018). The need to reassess dietary fiber requirements in
healthy and critically ill patients. Gastroenterol. Clin. North Am. 47, 219–229.
O’Keefe, S.J., Li, J.V., Lahti, L., Ou, J., Carbonero, F., Mohammed, K., Posma,
J.M., Kinross, J., Wahl, E., Ruder, E., et al. (2015). Fat, fibre and cancer risk in
African Americans and rural Africans. Nat. Commun. 6, 6342.
Ott, S.J., and Schreiber, S. (2006). Reduced microbial diversity in inflammatory
bowel diseases. Gut 55, 1207.
Pedersen, C., Lefevre, S., Peters, V., Patterson, M., Ghatei, M.A., Morgan,
L.M., and Frost, G.S. (2013). Gut hormone release and appetite regulation in
healthy non-obese participants following oligofructose intake. A dose-escala-
tion study. Appetite 66, 44–53.
Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y.,
Shen, D., et al. (2012). A metagenome-wide association study of gut micro-
biota in type 2 diabetes. Nature 490, 55–60.
Raffatellu, M., Santos, R.L., Verhoeven, D.E., George, M.D., Wilson, R.P.,
Winter, S.E., Godinez, I., Sankaran, S., Paixao, T.A., Gordon, M.A., et al.
(2008). Simian immunodeficiency virus-induced mucosal interleukin-17 defi-
ciency promotes Salmonella dissemination from the gut. Nat. Med. 14,
421–428.
Reddy, B.S., Engle, A., Simi, B., and Goldman, M. (1992). Effect of dietary fiber
on colonic bacterial enzymes and bile acids in relation to colon cancer. Gastro-
enterology 102, 1475–1482.
Reed, S., Neuman, H., Moscovich, S., Glahn, R.P., Koren, O., and Tako, E.
(2015). Chronic zinc deficiency alters chick gut microbiota composition and
function. Nutrients 7, 9768–9784.
Rescigno, M. (2014). Intestinal microbiota and its effects on the immune sys-
tem. Cell. Microbiol. 16, 1004–1013.
Sadar, S.S., Vyawahare, N.S., and Bodhankar, S.L. (2016). Ferulic acid amelio-
rates TNBS-induced ulcerative colitis through modulation of cytokines, oxida-
tive stress, iNOs, COX-2, and apoptosis in laboratory rats. EXCLI J. 15,
482–499.
Schaafsma, G., and Slavin, J.L. (2014). Significance of inulin fructans in the hu-
man diet. Compr. Rev. Food Sci. Food Saf. 14, 37–47.
Schnorr, S.L., Candela, M., Rampelli, S., Centanni, M., Consolandi, C., Basa-
glia, G., Turroni, S., Biagi, E., Peano, C., Severgnini, M., et al. (2014). Gut
microbiome of the Hadza hunter-gatherers. Nat. Commun. 5, 3654.
Schroeder, B.O., and Ba €ckhed, F. (2016). Signals from the gut microbiota to
distant organs in physiology and disease. Nat. Med. 22, 1079–1089.
Schroeder, B.O., Birchenough, G.M.H., Ståhlman, M., Arike, L., Johansson,
€ckhed, F. (2018). Bifidobacteria or fiber protects
M.E.V., Hansson, G.C., and Ba
against diet-induced microbiota-mediated colonic mucus deterioration. Cell
Host Microbe 23, 27–40.e7.
Schwarzer, M., Makki, K., Storelli, G., Machuca-Gayet, I., Srutkova, D., Her-
manova, P., Martino, M.E., Balmand, S., Hudcovic, T., Heddi, A., et al.
(2016). Lactobacillus plantarum strain maintains growth of infant mice during
chronic undernutrition. Science 351, 854–857.
714 Cell Host & Microbe 23, June 13, 2018
Cell Host & Microbe
Review
Sluijs, I., Forouhi, N.G., Beulens, J.W., van der Schouw, Y.T., Agnoli, C., Ar-
riola, L., Balkau, B., Barricarte, A., Boeing, H., Bueno-de-Mesquita, H.B.,
et al.; InterAct Consortium (2012). The amount and type of dairy product intake
and incident type 2 diabetes: results from the EPIC-InterAct Study. Am. J. Clin.
Nutr. 96, 382–390.
Smith, P.M., Howitt, M.R., Panikov, N., Michaud, M., Gallini, C.A., Bohlooly-Y,
M., Glickman, J.N., and Garrett, W.S. (2013). The microbial metabolites, short-
chain fatty acids, regulate colonic Treg cell homeostasis. Science 341,
569–573.
Smits, S.A., Leach, J., Sonnenburg, E.D., Gonzalez, C.G., Lichtman, J.S.,
Reid, G., Knight, R., Manjurano, A., Changalucha, J., Elias, J.E., et al. (2017).
Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of
Tanzania. Science 357, 802–806.
Sommer, F., Ståhlman, M., Ilkayeva, O., Arnemo, J.M., Kindberg, J., Josefs-
son, J., Newgard, C.B., Fröbert, O., and Ba €ckhed, F. (2016). The gut
microbiota modulates energy metabolism in the hibernating brown bear Ursus
arctos. Cell Rep. 14, 1655–1661.
Sonnenburg, E.D., and Sonnenburg, J.L. (2014). Starving our microbial self:
the deleterious consequences of a diet deficient in microbiota-accessible
carbohydrates. Cell Metab. 20, 779–786.
Sonnenburg, J.L., Xu, J., Leip, D.D., Chen, C.H., Westover, B.P., Weatherford,
J., Buhler, J.D., and Gordon, J.I. (2005). Glycan foraging in vivo by an intestine-
adapted bacterial symbiont. Science 307, 1955–1959.
Sonnenburg, E.D., Smits, S.A., Tikhonov, M., Higginbottom, S.K., Wingreen,
N.S., and Sonnenburg, J.L. (2016). Diet-induced extinctions in the gut micro-
biota compound over generations. Nature 529, 212–215.
Stephen, A.M., Champ, M.M., Cloran, S.J., Fleith, M., van Lieshout, L., Mej-
born, H., and Burley, V.J. (2017). Dietary fibre in Europe: current state of
knowledge on definitions, sources, recommendations, intakes and relation-
ships to health. Nutr. Res. Rev. 30, 149–190.
Tomaro-Duchesneau, C., Saha, S., Malhotra, M., Coussa-Charley, M., Ka-
houli, I., Jones, M.L., Labbé, A., and Prakash, S. (2012). Probiotic ferulic
acid esterase active Lactobacillus fermentum NCIMB 5221 APA microcap-
sules for oral delivery: preparation and in vitro characterization. Pharmaceuti-
cals (Basel) 5, 236–248.
Trinidad, T.P., Wolever, T.M., and Thompson, L.U. (1997). Effect of short chain
fatty acids on calcium absorption in humans. Adv. Exp. Med. Biol. 427,
183–189.
Trompette, A., Gollwitzer, E.S., Yadava, K., Sichelstiel, A.K., Sprenger, N.,
Ngom-Bru, C., Blanchard, C., Junt, T., Nicod, L.P., Harris, N.L., and Marsland,
B.J. (2014). Gut microbiota metabolism of dietary fiber influences allergic
airway disease and hematopoiesis. Nat. Med. 20, 159–166.
Walker, A.W., Ince, J., Duncan, S.H., Webster, L.M., Holtrop, G., Ze, X., Brown,
D., Stares, M.D., Scott, P., Bergerat, A., et al. (2011). Dominant and diet-
responsive groups of bacteria within the human colonic microbiota. ISME J.
5, 220–230.
Walter, J., Britton, R.A., and Roos, S. (2011). Host-microbial symbiosis in the
vertebrate gastrointestinal tract and the Lactobacillus reuteri paradigm.
Proc. Natl. Acad. Sci. USA 108 (Suppl 1 ), 4645–4652.
Wang, T., Cai, G., Qiu, Y., Fei, N., Zhang, M., Pang, X., Jia, W., Cai, S., and
Zhao, L. (2012). Structural segregation of gut microbiota between colorectal
cancer patients and healthy volunteers. ISME J. 6, 320–329.
Windey, K., De Preter, V., and Verbeke, K. (2012). Relevance of protein fermen-
tation to gut health. Mol. Nutr. Food Res. 56, 184–196.
Wrzosek, L., Miquel, S., Noordine, M.L., Bouet, S., Joncquel Chevalier-Curt,
M., Robert, V., Philippe, C., Bridonneau, C., Cherbuy, C., Robbe-Masselot,
C., et al. (2013). Bacteroides thetaiotaomicron and Faecalibacterium praus-
nitzii influence the production of mucus glycans and the development of
goblet cells in the colonic epithelium of a gnotobiotic model rodent. BMC
Biol. 11, 61.
Wu, G.D., Chen, J., Hoffmann, C., Bittinger, K., Chen, Y.Y., Keilbaugh, S.A.,
Bewtra, M., Knights, D., Walters, W.A., Knight, R., et al. (2011). Linking long-
term dietary patterns with gut microbial enterotypes. Science 334, 105–108.
Yang, H., Youm, Y.H., Vandanmagsar, B., Rood, J., Kumar, K.G., Butler, A.A.,
and Dixit, V.D. (2009). Obesity accelerates thymic aging. Blood 114,
3803–3812.
Cell Host & Microbe
Review
Yatsunenko, T., Rey, F.E., Manary, M.J., Trehan, I., Dominguez-Bello, M.G.,
Contreras, M., Magris, M., Hidalgo, G., Baldassano, R.N., Anokhin, A.P.,
et al. (2012). Human gut microbiome viewed across age and geography. Na-
ture 486, 222–227.
Ze, X., Duncan, S.H., Louis, P., and Flint, H.J. (2012). Ruminococcus bromii is a
keystone species for the degradation of resistant starch in the human colon.
ISME J. 6, 1535–1543.
Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., Weinberger, A.,
Ben-Yacov, O., Lador, D., Avnit-Sagi, T., Lotan-Pompan, M., et al. (2015).
Personalized nutrition by prediction of glycemic responses. Cell 163,
1079–1094.
Zhao, L., Zhang, F., Ding, X., Wu, G., Lam, Y.Y., Wang, X., Fu, H., Xue, X., Lu,
C., Ma, J., et al. (2018). Gut bacteria selectively promoted by dietary fibers alle-
viate type 2 diabetes. Science 359, 1151–1156.
Zou, J., Chassaing, B., Singh, V., Pellizzon, M., Ricci, M., Fythe, M.D., Kumar,
M.V., and Gewirtz, A.T. (2018). Fiber-mediated nourishment of gut microbiota
protects against diet-induced obesity by restoring IL-22-mediated colonic
health. Cell Host Microbe 23, 41–53.e4.
Cell Host & Microbe 23, June 13, 2018 715